(Trimethoxyphenylamino) pyrimidinyl formulations

ABSTRACT

There are provided pharmaceutical compositions comprising greater than 15% w/w of a compound of Formula (I) as defined herein and/or hydrate thereof and an amount of one or more effervescent agents that is sufficient to provide satisfactory in vitro dissolution; and further comprising one or more pharmaceutically acceptable ingredients; and to processes for obtaining them.

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Application No. 61/512,621 filed on 28 Jul. 2011.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical/formulation chemistry.The invention is understood to apply generally to formulations ofcompounds which contain an increased percent loading of the activeingredient. As a preferred aspect, provided herein are formulations of(6-(5-fluoro-2-(3,4,5-trimethoxyphenylamino)pyrimidin-4-ylamino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methylphosphate disodium salt (Compound I) which contain an increased percentloading of Compound I. The formulations are useful for treating avariety of diseases including, but not limited to, lymphoma, immune(idiopathic) thrombocytopenia purpura (ITP), and rheumatoid arthritis(RA).

BACKGROUND OF THE INVENTION

In the manufacture of pharmaceutical formulations, it may be desirablefor the drug to be administered using the smallest possible number oftablets. Thus it may be desirable for a patient to take the requireddose of a drug in a single tablet rather than in more than one tablet,or in two tablets rather than in more than two tablets. Accordingly, itmay be desirable for a pharmaceutical formulation to contain anincreased percent loading of the active ingredient. However, it is knownthat increasing the percent loading of active ingredient may lead to apharmaceutical formulation which exhibits unsatisfactory and/or variabledissolution or to a formulation which exhibits unsatisfactory and/orvariable bioavailability. Such formulations may be unsuitable for use bypatients.

Compound I (below) is disclosed in international patent applicationWO2006/078846.

Compound I is a pro-drug of Compound II (below). Compound II isdisclosed in international patent application WO2005/016893.

Hydrolytically stable pharmaceutical formulations of Compound I whichinclude a water sequestering agent and which are prepared by a wetgranulation process are disclosed in international patent applicationWO2009/061909.

Javaid et al (J. Pharm. Sci. 61 (9) 1972 pp 1370-1373) studied theeffect of various classes of buffering agents on the dissolution ofaspirin from tablet formulations.

Compound I is currently in clinical studies for the treatment of avariety of diseases such as lymphoma, ITP and RA. Dosing is currentlydone with orally delivered tablets with a tablet strength of 50 mg.These tablets exhibit satisfactory dissolution at low pH. However, thesetablets contain a relatively low percent loading (12.5% w/w) of CompoundI.

Tablets with a tablet strength of 100 mg contain an increased percentloading of Compound I. However, these tablets may exhibit unsatisfactoryand/or variable dissolution at low pH. Furthermore, these tablets mayexhibit unsatisfactory and/or variable bioavailability of the activeingredient.

It is desirable, therefore, to produce new pharmaceutical formulationsof Compound I which overcome at least in part the above problems.

DESCRIPTION OF THE INVENTION

This invention is generally directed to formulations of compounds whichcontain an increased percent loading of the compound of formula (I), inparticular to formulations which contain an increased percent loading ofactive ingredient and exhibit satisfactory dissolution at low pH.

The compound of formula (I) (known hereafter as “Formula (I)”) is shownbelow:

wherein each X⁺ represents a monovalent cation, for example a monovalentmetal cation, such as a sodium cation (Na⁺), a potassium cation (K⁺) ora lithium cation (Li⁺); or wherein X⁺ and X⁺ are taken together torepresent a divalent cation X²⁺, for example a divalent metal cation,such as a magnesium cation (Mg²⁺), a calcium cation (Ca²⁺) or a bariumcation (Ba²⁺);and/or hydrates thereof (such as the hexahydrate).

For example, Formula (I) may be in the form of Compound (I) above.

In another particular example, Formula (I) may be in the hexahydrateform of Compound (I) (which form is known hereafter as “Formula (II)”).The compound of Formula (II) is shown below.

In particular, this invention provides a pharmaceutical compositioncomprising Formula (I) and/or hydrate thereof and one or moreeffervescent agents allowing the manufacture of tablets with anincreased percent loading of Formula (I) and/or a satisfactorydissolution at low pH.

In a still further aspect, this invention provides a pharmaceuticalcomposition comprising Formula (I) and/or hydrate thereof and sodiumhydrogen carbonate allowing the manufacture of tablets with an increasedpercent loading of Formula (I) and/or a satisfactory dissolution at lowpH.

In a yet further aspect, this invention provides a pharmaceuticalcomposition comprising Formula (I) and/or hydrate thereof and potassiumhydrogen carbonate allowing the manufacture of tablets with an increasedpercent loading of Formula (I) and/or a satisfactory dissolution at lowpH.

In a still further aspect, this invention provides a pharmaceuticalcomposition comprising Formula (I) and/or hydrate thereof and magnesiumcarbonate allowing the manufacture of tablets with an increased percentloading of Formula (I) and/or a satisfactory dissolution at low pH.

In a still further aspect, this invention provides a pharmaceuticalcomposition comprising Formula (I) and/or hydrate thereof and sodiumcarbonate allowing the manufacture of tablets with an increased percentloading of Formula (I) and/or a satisfactory dissolution at low pH.

In a still further aspect, this invention provides a pharmaceuticalcomposition comprising Formula (I) and/or hydrate thereof and calciumcarbonate allowing the manufacture of tablets with an increased percentloading of Formula (I) and/or a satisfactory dissolution at low pH.

In a still further aspect, this invention provides a pharmaceuticalcomposition comprising Formula (I) and/or hydrate thereof and potassiumcarbonate allowing the manufacture of tablets with an increased percentloading of Formula (I) and/or a satisfactory dissolution at low pH.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and an amount of one or more effervescent agents that issufficient to provide satisfactory in vitro dissolution; and furthercomprising one or more pharmaceutically acceptable ingredients.

In another aspect of the invention, there is provided a pharmaceuticalcomposition in unit dosage form comprising greater than or equal to 60mg of Formula (I) and/or hydrate thereof (for example 60 mg, 70 mg, 80mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170mg, 180 mg, 190 mg or 200 mg) and an amount of one or more effervescentagents that is sufficient to provide satisfactory in vitro dissolution;and further comprising one or more pharmaceutically acceptableingredients. For the avoidance of doubt, each of the previous integersrepresents a separate and independent aspect of the invention.

In another aspect of the invention a unit dosage form of thepharmaceutical composition comprises between about 60 mg to about 300 mgof Formula (I) and/or hydrate thereof.

In another aspect of the invention a unit dosage form of thepharmaceutical composition comprises between about 60 mg to about 250 mgof Formula (I) and/or hydrate thereof.

In a still further aspect, a unit dosage form of the pharmaceuticalcomposition comprises between about 100 mg to about 200 mg of Formula(I) and/or hydrate thereof.

In a yet further aspect, a unit dosage form of the pharmaceuticalcomposition comprises between about 125 mg to about 190 mg of Formula(I) and/or hydrate thereof.

In a specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 63 mg±3 mg of Formula (I) and/orhydrate thereof.

In a specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 126 mg±13 mg of Formula (I) and/orhydrate thereof.

In a further specific aspect of the invention, a unit dosage form of thepharmaceutical composition comprises 190 mg±19 mg of Formula (I) and/orhydrate thereof.

In another aspect of the invention the pharmaceutical compositioncomprises between about 15% w/w to about 60% w/w of Formula (I) and/orhydrate thereof.

In a further aspect, the pharmaceutical composition comprises betweenabout 20% w/w to about 50% w/w of Formula (I) and/or hydrate thereof.

In a still further aspect, the pharmaceutical composition comprisesbetween about 25% w/w to about 40% w/w of Formula (I) and/or hydratethereof.

In another aspect of the invention the pharmaceutical compositioncomprises greater than or equal to 25% w/w of Formula (I) and/or hydratethereof.

In a specific aspect of the invention, the pharmaceutical compositioncomprises 25%±2.5% w/w of Formula (I) and/or hydrate thereof.

In a further specific aspect of the invention, the pharmaceuticalcomposition comprises 38%±3.8% of Formula (I) and/or hydrate thereof.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises less than or equal to 30% w/w of one or moreeffervescent agents.

In a still further aspect of the invention, the pharmaceuticalcomposition comprises less than or equal to 25% w/w of one or moreeffervescent agents.

In a further aspect, the pharmaceutical composition comprises less thanor equal to 20% w/w of one or more effervescent agents.

In a still further aspect, the pharmaceutical composition comprises lessthan or equal to 15% w/w of one or more effervescent agents.

In a still further aspect, the pharmaceutical composition comprises lessthan or equal to 10% w/w of one or more effervescent agents.

In a yet further aspect, the pharmaceutical composition comprisesgreater than or equal to about 5% w/w of one or more effervescentagents, for example between about 5% to 50%, for example between about5% to 40%, for example between about 5% to 30%, for example betweenabout 5% to 25%, for example between about 5% to 20%, for examplebetween about 5% to 15%, for example between about 5% to 10%. For theavoidance of doubt, each of the previous examples represents a separateand independent aspect of the invention.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and less than or equal to 25% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and less than or equal to 20% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and less than or equal to 15% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a pharmaceuticalcomposition comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and less than or equal to 10% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a unit dosageform comprising greater than or equal to 60 mg of Formula (I) and/orhydrate thereof and less than or equal to 110 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a unit dosageform comprising greater than or equal to 60 mg of Formula (I) and/orhydrate thereof and less than or equal to 75 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a still further aspect of the invention, there is provided a unitdosage form comprising greater than or equal to 125 mg of Formula (I)and/or hydrate thereof and less than or equal to 110 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a still further aspect of the invention, there is provided a unitdosage form comprising greater than or equal to 125 mg of Formula (I)and/or hydrate thereof and less than or equal to 75 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a yet further aspect of the invention, there is provided a unitdosage form comprising greater than or equal to 190 mg of Formula (I)and/or hydrate thereof and less than or equal to 110 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a yet further aspect of the invention, there is provided a unitdosage form comprising greater than or equal to 190 mg of Formula (I)and/or hydrate thereof and less than or equal to 75 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a yet further aspect of the invention, there is provided a unitdosage form comprising greater than or equal to 225 mg of Formula (I)and/or hydrate thereof and less than or equal to 150 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a yet further aspect of the invention, there is provided a unitdosage form comprising greater than or equal to 225 mg of Formula (I)and/or hydrate thereof and less than or equal to 110 mg of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a still further embodiment of the invention, the pharmaceuticalcomposition and/or unit dosage form does not comprise an acidifyingingredient (for example does not comprise citric acid). For theavoidance of doubt the term “acidifying ingredient” does not include thecompound of Formula (I) or the free acid thereof or hydrate thereof.

In a further aspect of the invention, optional ingredients which can beadded to the pharmaceutical composition include one or more of thefollowing:

-   -   a) fillers which, when employed, range between for example about        35 to about 75 weight percent (e.g. about 50 to about 70 weight        percent) of the dry formulation;    -   b) binding agents which, when employed range between for example        about 2 to about 8 weight percent of the dry formulation;    -   c) lubricants which, when employed, range from between about        0.25 and 2.0 weight percent of the dry formulation;    -   d) disintegrants which, when employed, range from between about        0.5 and 10.0 weight percent (e.g. about 5 weight percent) of the        dry formulation; and    -   e) water sequestering agents, which, when employed, range from        between about 2 weigh percent and 40 weight percent of the dry        formulation.

In a further aspect of the invention, the pharmaceutical compositionfurther comprises one or more additional ingredients independentlyselected from, for example

-   -   a) fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c        or Pearlitol 160c) or microcrystalline celluloses (e.g. MCC        Avicel PH 102, Emcocel 90M, etc.);    -   b) binding agents such as Plasdone K29/32, Povidone,        microcrystalline celluloses or Kollidon K30;    -   c) lubricants such as magnesium stearate;    -   d) disintegrants such as sodium starch glycolate, for example        ExploTab or Glycolys LV;    -   e) Water sequestering agents such as starch (e.g. sodium starch        glycolate), magnesium sulfate, calcium chloride, silica, kaolin,        microcrystalline celluloses etc.

In another aspect of the invention, there is provided a tabletcomprising greater than 15% w/w of Formula (I) and/or hydrate thereofand an amount of one or more effervescent agents that is sufficient toprovide satisfactory in vitro dissolution; and further comprising one ormore pharmaceutically acceptable ingredients.

In another aspect of the invention, there is provided a tabletcomprising greater than or equal to 60 mg of Formula (I) and/or hydratethereof (for example 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg,130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg or 200 mg) and anamount of one or more effervescent agents (that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients. For the avoidance of doubt,each of the previous integers represents a separate and independentaspect of the invention.

In another aspect of the invention, the tablet comprises between about60 mg to about 300 mg of Formula (I) and/or hydrate thereof.

In another aspect of the invention the tablet comprises between about 60mg to about 250 mg of Formula (I) and/or hydrate thereof.

In a still further aspect, the tablet comprises between about 100 mg toabout 200 mg of Formula (I) and/or hydrate thereof.

In a yet further aspect, the tablet comprises between about 125 mg toabout 190 mg of Formula (I) and/or hydrate thereof.

In a specific aspect of the invention, the tablet comprises 63 mg±3 mgof Formula (I) and/or hydrate thereof.

In a specific aspect of the invention, the tablet comprises 126 mg±13 mgof Formula (I) and/or hydrate thereof.

In a further specific aspect of the invention, the tablet comprises 190mg±19 mg of Formula (I) and/or hydrate thereof.

In another aspect of the invention the tablet comprises between about15% w/w to about 60% w/w of Formula (I) and/or hydrate thereof.

In a further aspect, the tablet comprises between about 20% w/w to about50% w/w of Formula (I) and/or hydrate thereof.

In a still further aspect, the tablet comprises between about 25% w/w toabout 40% w/w of Formula (I) and/or hydrate thereof.

In another aspect of the invention the tablet comprises greater than orequal to 25% w/w of Formula (I) and/or hydrate thereof.

In a specific aspect of the invention, the tablet comprises 25%±2.5% w/wof Formula (I) and/or hydrate thereof.

In a further specific aspect of the invention, the tablet comprises38%±3.8% of Formula (I) and/or hydrate thereof.

In a still further aspect of the invention, the tablet comprises lessthan or equal to 30% w/w of one or more effervescent agents.

In a further aspect, the tablet comprises less than or equal to 20% w/wof one or more effervescent agents.

In a still further aspect, the tablet comprises less than or equal to15% w/w of one or more effervescent agents.

In a still further aspect, the tablet comprises less than or equal to10% w/w of one or more effervescent agents.

In a further aspect of the invention, the tablet comprises less than orequal to 75 mg of one or more effervescent agents.

In a yet further aspect, the tablet comprises greater than or equal toabout 5% w/w of one or more effervescent agents, for example betweenabout 5% to 50%, for example between about 5% to 40%, for examplebetween about 5% to 30%, for example between about 5% to 25%, forexample between about 5% to 20%, for example between about 5% to 15%,for example between about 5% to 10%. For the avoidance of doubt, each ofthe previous examples represents a separate and independent aspect ofthe invention.

In a further aspect of the invention, there is provided a tabletcomprising greater than 15% w/w of Formula (I) and/or hydrate thereofand less than or equal to 25% w/w of one or more effervescent agents;and further comprising one or more pharmaceutically acceptableingredients.

In a further aspect of the invention, there is provided a tabletcomprising greater than 15% w/w of Formula (I) and/or hydrate thereofand less than or equal to 20% w/w of one or more effervescent agents;and further comprising one or more pharmaceutically acceptableingredients.

In a further aspect of the invention, there is provided a tabletcomprising greater than 15% w/w of Formula (I) and/or hydrate thereofand less than or equal to 15% w/w of one or more effervescent agents;and further comprising one or more pharmaceutically acceptableingredients.

In a further aspect of the invention, there is provided a tabletcomprising greater than 15% w/w of Formula (I) and/or hydrate thereofand less than or equal to 10% w/w of one or more effervescent agents;and further comprising one or more pharmaceutically acceptableingredients.

In a further aspect of the invention, there is provided a tabletcomprising greater than or equal to 60 mg of Formula (I) and/or hydratethereof and less than or equal to 110 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a further aspect of the invention, there is provided a tabletcomprising greater than or equal to 60 mg of Formula (I) and/or hydratethereof and less than or equal to 75 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a still further aspect of the invention, there is provided a tabletcomprising greater than or equal to 125 mg of Formula (I) and/or hydratethereof and less than or equal to 110 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a still further aspect of the invention, there is provided a tabletcomprising greater than or equal to 125 mg of Formula (I) and/or hydratethereof and less than or equal to 75 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a yet further aspect of the invention, there is provided a tabletcomprising greater than or equal to 190 mg of Formula (I) and/or hydratethereof and less than or equal to 110 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a yet further aspect of the invention, there is provided a tabletcomprising greater than or equal to 190 mg of Formula (I) and/or hydratethereof and less than or equal to 75 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a yet further aspect of the invention, there is provided a tabletcomprising greater than or equal to 225 mg of Formula (I) and/or hydratethereof and less than or equal to 150 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a yet further aspect of the invention, there is provided a tabletcomprising greater than or equal to 225 mg of Formula (I) and/or hydratethereof and less than or equal to 110 mg of one or more effervescentagents; and further comprising one or more pharmaceutically acceptableingredients.

In a still further embodiment of the invention, the tablet does notcomprise an acidifying ingredient (for example does not comprise citricacid). For the avoidance of doubt the term “acidifying ingredient” doesnot include the compound of Formula (I) or the free acid thereof or ahydrate thereof.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral administration.

These dosage forms will usually include one or more pharmaceuticallyacceptable excipients which may be selected, for example, fromadjuvants, carriers, binders, lubricants, diluents, stabilising agents,buffering agents, emulsifying agents, viscosity-regulating agents,surfactants, preservatives, flavourings or colorants. It will beunderstood that an individual excipient may be multifunctional. Examplesof pharmaceutically acceptable excipients are described in the Handbookof Pharmaceutical Excipients (Fifth Edition, 2005, edited by Ray C.Rowe, Paul J. Sheskey and Sian C. Owen, published by the AmericanPharmaceutical Association and the Pharmaceutical Press). The activeingredients of the present invention may be administered by oral orparenteral (e.g. intravenous, subcutaneous, intramuscular orintraarticular) administration using conventional systemic dosage forms,such as tablets, capsules, pills, powders, aqueous or oily solutions orsuspensions, emulsions and sterile injectable aqueous or oily solutionsor suspensions. The active ingredients may also be delivered to the lungand/or airways via oral administration in the form of a solution,suspension, aerosol or dry powder formulation. As will be understood bythose skilled in the art, the most appropriate method of administeringthe active ingredients is dependent on a number of factors.

It will be understood that the therapeutic dose of each activeingredient administered in accordance with the present invention willvary depending upon the particular active ingredient employed, the modeby which the active ingredient is to be administered, and the conditionor disorder to be treated.

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

In a further aspect of the invention, optional ingredients which can beadded to the compositions disclosed herein include one or more of thefollowing:

-   -   a) fillers which, when employed, range between for example about        35 to about 75 weight percent (e.g. about 50 to about 70 weight        percent) of the dry formulation;    -   b) binding agents which, when employed range between for example        about 2 to about 8 weight percent of the dry formulation;    -   c) lubricants which, when employed, range from between about        0.25 and 2.0 weight percent of the dry formulation;    -   d) disintegrants which, when employed, range from between about        0.5 and 10.0 weight percent (e.g. about 5 weight percent) of the        dry formulation; and    -   a) water sequestering agents, which, when employed, range from        between about 2 weigh percent and 40 weight percent of the dry        formulation;

In a further aspect of the invention, the tablet further comprises oneor more additional ingredients independently selected from, for example:

-   -   a) fillers such as mannitol (e.g. Pearlitol 50c, Peralitol 120c        or Pearlitol 160c) or microcrystalline celluloses (e.g. MCC        Avicel PH 102, Emcocel 90M, etc.);    -   b) binding agents such as Plasdone K29/32, Povidone,        microcrystalline celluloses or Kollidon K30;    -   c) lubricants such as magnesium stearate;    -   d) disintegrants such as sodium starch glycolate, for example        ExploTab or Glycolys LV;    -   a) Water sequestering agents such as starch (e.g. sodium starch        glycolate), calcium chloride, silica, kaolin, microcrystalline        celluloses etc.

In a further aspect of the invention, the pharmaceutical composition orunit dosage form comprises the compound of Formula (I) and/or hydratethereof, one or more effervescent agents and a filler (such asmannitol). In a further aspect of the invention, the pharmaceuticalcomposition or unit dosage form comprises the compound of Formula (I)and/or hydrate thereof, one or more effervescent agents, a filler (suchas mannitol) and a binding agent (such as Povidone). In a further aspectof the invention, the pharmaceutical composition or unit dosage formcomprises the compound of Formula (I) and/or hydrate thereof, one ormore effervescent agents, a filler (such as mannitol), a binding agent(such as Povidone) and a disintegrant (such as sodium starch glycolate).In another aspect the pharmaceutical composition or unit dosage formcomprises the compound of Formula (II), one or more effervescent agents,a filler (such as mannitol), a binding agent (such as Povidone), adisintegrant (such as sodium starch glycolate) and a lubricant (such asmagnesium stearate).

In a yet further aspect of the invention, the pharmaceutical compositioncomprises the following components by weight:

Composition 1 (mg) Formula (II) 126 Mannitol 249 Sodium hydrogen 75carbonate Sodium starch 25 glycolate Povidone 15 Magnesium stearate 10Composition 2 (mg) Formula (II) 190 Mannitol 185 Sodium hydrogen 75carbonate Sodium starch 25 glycolate Povidone 15 Magnesium stearate 10Composition 3 (mg) Formula (II) 63 Mannitol 62 Sodium hydrogen 25carbonate Sodium starch 8 glycolate Povidone 5 Magnesium stearate 3

In a yet further aspect of the invention, the pharmaceutical compositioncomprises the following components (% w/w):

Composition 1 (% w/w) Formula (II) 25 Mannitol 50 Sodium hydrogen 15carbonate Sodium starch 5 glycolate Povidone 3 Magnesium stearate 2Composition 2 and 3 (% w/w) Formula (II) 38 Mannitol 37 Sodium hydrogen15 carbonate Sodium starch 5 glycolate Povidone 3 Magnesium stearate 2

In a still further aspect, the invention comprises a tablet formed fromthe pressing of Composition 1 and/or Composition 2 into tablet form. Ina still further aspect, the invention comprises a tablet formed from thepressing of Composition 3 into tablet form.

In a separate aspect of the invention, there is provided a process forthe preparation of a pharmaceutical composition, as hereinbeforedefined, which process comprises bringing into association Formula (I)and/or hydrate thereof with a pharmaceutically acceptable adjuvant,diluents or carrier.

In a further aspect of the invention, there is provided a process forthe preparation of a pharmaceutical composition which process comprisesmixing Formula (I) and/or hydrate thereof with one or more effervescentagents optionally in the presence of one or more pharmaceuticallyacceptable ingredients (Step A). In a further aspect, Step A is carriedout in the presence of one or more fillers (such as mannitol) andoptionally in the presence of one or more pharmaceutically acceptableingredients. In a still further aspect, Step A is carried out in thepresence of one or more fillers (such as mannitol) and optionally in thepresence of one or more binding agents and/or one or more disintegrants.

In a further aspect of the invention, there is provided a furtherprocess for the preparation of a pharmaceutical composition as definedabove which process comprises adding purified water and/or bindersolution into the powder mixture from Step A above and mixing to formenlarged granules and optionally passing through a filter screen tobreak-up large agglomerates (Step B). In a further aspect between about10% and 45% by weight of purified water is added into the powdermixture.

In a further aspect of the invention, there is provided a furtherprocess for the preparation of a pharmaceutical composition whichprocess comprises drying the enlarged granules produced in Step B aboveuntil an LOD of less than 10% (e.g. less than 5%) is achieved, toprovide dried granules (Step C).

In a further aspect of the invention there is provided a process for thepreparation of a pharmaceutical composition which process (wetgranulation process) comprises:

-   -   a) blending Formula (I) and/or hydrate thereof with one or more        effervescent agents, one or more fillers (such as mannitol) and        optionally in the presence of one or more binding agents and/or        one or more disintegrants and/or one or more other excipients;    -   b) adding between about 10% and 45% by weight of purified water        and/or binder solution into the powder mixture of a) above and        mixing to form enlarged granules and optionally passing through        a filter screen to break-up large agglomerates; and    -   c) drying the enlarged granules produced in b) above until an        LOD of less than 10% (e.g. less than 5%) is achieved, to provide        dried granules.

The dried granules prepared in the methods above are typically betweenabout 25 μm to about 2000 μm in diameter.

In another of its method aspects, this invention further comprisesmilling the dried granules. In one aspect, the dried granules are milledso that about 90 weight percent have a particle size between about 25 μmto about 2000 μm in diameter.

In yet another aspect, the dried, milled, granules are mixed with alubricant until homogenous, and then the resulting pharmaceuticalcomposition is tabletted. Suitable lubricants include stearic acid (e.g.magnesium stearate), colloidal silica and talc.

In an alternative aspect of the invention, the lubricant (such asmagnesium stearate) can be added to the dry granules prior to milling,and then the resulting pharmaceutical composition is milled and thentabletted.

In another aspect, this invention provides a wet granulation formulationcomprising greater than 15% w/w of Formula (I) and/or hydrate thereofand an amount of an effervescent that is sufficient to providesatisfactory in vitro dissolution; and further comprising one or morepharmaceutically acceptable ingredients.

In another aspect of the invention the wet granulation formulationcomprises between about 15% w/w to about 60% w/w of Formula (I) and/orhydrate thereof.

In a further aspect, the wet granulation formulation comprises betweenabout 20% w/w to about 50% w/w of Formula (I) and/or hydrate thereof.

In a still further aspect, the wet granulation formulation comprisesbetween about 25% w/w to about 40% w/w of Formula (I) and/or hydratethereof.

In another aspect of the invention the wet granulation formulationcomprises greater than or equal to 25% w/w of Formula (I) and/or hydratethereof.

In a specific aspect of the invention, the wet granulation formulationcontains 25%±2.5% w/w of Formula (I) and/or hydrate thereof.

In a further specific aspect of the invention, the wet granulationformulation contains 38%±3.8% of Formula (I) and/or hydrate thereof.

In a still further aspect of the invention, the wet granulationformulation comprises less than or equal to 30% w/w of one or moreeffervescent agents.

In a further aspect, the wet granulation formulation comprises less thanor equal to 25% w/w of one or more effervescent agents.

In a further aspect, the wet granulation formulation comprises less thanor equal to 20% w/w of one or more effervescent agents.

In a still further aspect, the wet granulation formulation comprisesless than or equal to 15% w/w of one or more effervescent agents.

In a still further aspect, the wet granulation formulation comprisesless than or equal to 10% w/w of one or more effervescent agents.

In a yet further aspect, the wet granulation formulation comprisesgreater than or equal to about 5% w/w of one or more effervescentagents, for example between about 5% to 50%, for example between about5% to 40%, for example between about 5% to 30%, for example betweenabout 5% to 25%, for example between about 5% to 20%, for examplebetween about 5% to 15%, for example between about 5% to 10%. For theavoidance of doubt, each of the previous examples represents a separateand independent aspect of the invention.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 25% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 20% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 15% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a wetgranulation formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 10% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In another aspect of the invention the wet granulation formulationcomprises Formula (I) and/or hydrate thereof, water, one or moreeffervescent agents, filler(s), binding agent(s) and disintegrant(s).

In a still further embodiment of the invention, the wet granulationformulation does not comprise an acidifying ingredient (for example doesnot comprise citric acid). For the avoidance of doubt the term“acidifying ingredient” does not include the compound of Formula (I) orthe free acid thereof or a hydrate thereof.

In another aspect, this invention provides a tablet formed bycompressing the wet granulation formulation.

In a further aspect of the invention, there is provided a furtherprocess for the preparation of a pharmaceutical composition as definedabove which process comprises passing the mixture of Step A abovethrough a compactor to produce dry granules (Step D).

In a further aspect of the present invention there is provided a processfor the manufacture of a pharmaceutical composition which process(roller compaction process) comprises:

-   -   (a) blending Formula (I) and/or hydrate thereof with one or more        effervescent agents, one or more fillers (such as mannitol) and        optionally in the presence of one or more binding agents and/or        one or more disintegrants and/or one or more other excipients;    -   (b) passing the mixture of (a) above through a compactor to        produce dry granules.

The dried granules prepared in the methods above are typically betweenabout 25 μm to about 2000 μm in diameter.

In another of its method aspects, this invention further comprisesmilling the dried granules. In one aspect, the dried granules are milledso that about 90 weight percent have a particle size between about 25 μmto about 2000 μm in diameter.

In another aspect, a lubricant is added to the mixture of (a) aboveprior to passing through a compactor. Suitable lubricants includestearic acid (e.g. magnesium stearate), colloidal silica and talc.

In yet another aspect, the resulting pharmaceutical composition istabletted. In an alternative aspect of the invention, the lubricant(such as magnesium stearate) can be added to the dry granules prior tomilling, and then the resulting pharmaceutical composition is milled andthen tabletted.

In another aspect, this invention provides a roller compactionformulation comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and an amount of one or more effervescent agents that issufficient to provide satisfactory in vitro dissolution; and furthercomprising one or more pharmaceutically acceptable ingredients.

In another aspect of the invention the roller compaction formulationcomprises between about 15% w/w to about 60% w/w of Formula (I) and/orhydrate thereof.

In a further aspect, the roller compaction formulation comprises betweenabout 20% w/w to about 50% w/w of Formula (I) and/or hydrate thereof.

In a still further aspect, the roller compaction formulation comprisesbetween about 25% w/w to about 40% w/w of Formula (I) and/or hydratethereof.

In another aspect of the invention the roller compaction formulationcomprises greater than or equal to 25% w/w of Formula (I) and/or hydratethereof.

In a specific aspect of the invention, the roller compaction formulationcontains 25%±2.5% w/w of Formula (I) and/or hydrate thereof.

In a further specific aspect of the invention, the roller compactionformulation contains 38%±3.8% of Formula (I) and/or hydrate thereof.

In a still further aspect of the invention, the roller compactionformulation comprises less than or equal to 30% w/w of one or moreeffervescent agents.

In a further aspect, the roller compaction formulation comprises lessthan or equal to 20% w/w of one or more effervescent agents.

In a still further aspect, the roller compaction formulation comprisesless than or equal to 15% w/w of one or more effervescent agents.

In a still further aspect, the roller compaction formulation comprisesless than or equal to 10% w/w of one or more effervescent agents.

In a yet further aspect, the roller compaction formulation comprisesgreater than or equal to about 5% w/w of one or more effervescentagents, for example between about 5% to 50%, for example between about5% to 40%, for example between about 5% to 30%, for example betweenabout 5% to 25%, for example between about 5% to 20%, for examplebetween about 5% to 15%, for example between about 5% to 10%. For theavoidance of doubt, each of the previous examples represents a separateand independent aspect of the invention.

In a further aspect of the invention, there is provided a rollercompaction formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 25% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a rollercompaction formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 20% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a rollercompaction formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 15% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a rollercompaction formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 10% w/w of aneffervescent; and further comprising one or more pharmaceuticallyacceptable ingredients.

In another aspect of the invention the roller compaction formulationcomprises Formula (I) and/or hydrate thereof, one or more effervescentagents, filler(s), binding agent(s), lubricant(s) and disintegrant(s).

In a still further embodiment of the invention, the roller compactionformulation does not comprise an acidifying ingredient (for example doesnot comprise citric acid). For the avoidance of doubt the term“acidifying ingredient” does not include the compound of Formula (I) orthe free acid thereof or a hydrate thereof.

In another aspect, this invention provides a tablet formed bycompressing the roller compaction formulation.

In a further aspect of the invention there is provided a process for themanufacture of a pharmaceutical composition which process (directcompression process) comprises:

-   -   (a) blending Formula (I) and/or hydrate thereof with one or more        effervescent agents, one or more fillers (such as mannitol) and        optionally in the presence of one or more binding agents and/or        one or more disintegrants and/or one or more lubricants and/or        one or more other excipients;    -   (b) compressing the mixture of (a) above.

In another aspect of the invention the direct compression formulationcomprises Formula (I) and/or hydrate thereof, one or more effervescentagents, filler(s), binding agent(s), lubricant(s) and disintegrant(s).

In another aspect, this invention provides a tablet formed directly bycompressing the mixture of (a) above.

In another aspect, this invention provides a direct compressionformulation comprising greater than 15% w/w of Formula (I) and/orhydrate thereof and an amount of one or more effervescent agents that issufficient to provide satisfactory in vitro dissolution; and furthercomprising one or more pharmaceutically acceptable ingredients.

In another aspect of the invention the direct compression formulationcomprises between about 15% w/w to about 60% w/w of Formula (I) and/orhydrate thereof.

In a further aspect, the direct compression formulation comprisesbetween about 20% w/w to about 50% w/w of Formula (I) and/or hydratethereof.

In a still further aspect, the direct compression formulation comprisesbetween about 25% w/w to about 40% w/w of Formula (I) and/or hydratethereof.

In another aspect of the invention the direct compression formulationcomprises greater than or equal to 25% w/w of Formula (I) and/or hydratethereof.

In a specific aspect of the invention, the direct compressionformulation contains 25%±2.5% w/w of Formula (I) and/or hydrate thereof.

In a further specific aspect of the invention, the direct compressionformulation contains 38%±3.8% of Formula (I) and/or hydrate thereof.

In a still further aspect of the invention, the direct compressionformulation comprises less than or equal to 30% w/w of one or moreeffervescent agents.

In a further aspect, the direct compression formulation comprises lessthan or equal to 20% w/w of one or more effervescent agents.

In a still further aspect, the direct compression formulation comprisesless than or equal to 15% w/w of one or more effervescent agents.

In a still further aspect, the direct compression formulation comprisesless than or equal to 10% w/w of one or more effervescent agents.

In a yet further aspect, the direct compression formulation comprisesgreater than or equal to about 5% w/w of one or more effervescentagents, for example between about 5% to 50%, for example between about5% to 40%, for example between about 5% to 30%, for example betweenabout 5% to 25%, for example between about 5% to 20%, for examplebetween about 5% to 15%, for example between about 5% to 10%. For theavoidance of doubt, each of the previous examples represents a separateand independent aspect of the invention.

In a further aspect of the invention, there is provided a directcompression formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 25% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a directcompression formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 20% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a directcompression formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 15% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a further aspect of the invention, there is provided a directcompression formulation comprising greater than 15% w/w of Formula (I)and/or hydrate thereof and less than or equal to 10% w/w of one or moreeffervescent agents; and further comprising one or more pharmaceuticallyacceptable ingredients.

In a still further embodiment of the invention, the direct compressionformulation does not comprise an acidifying ingredient (for example doesnot comprise citric acid). For the avoidance of doubt the term“acidifying ingredient” does not include the compound of Formula (I) orthe free acid thereof or a hydrate thereof.

The pharmaceutical composition and/or tablet and/or wet granulationformulation and/or roller compaction formulation and/or directcompression formulation can additionally and optionally include acolourant, as long as it is approved and certified by the FDA. Forexample, exemplary colours include allura red, acid fuschin D,napthalone red B, food orange 8, eosin Y, phloxine B, erythrosine,natural red 4, carmine, red iron oxide, yellow iron oxide, black ironoxide, titanium dioxide and the like.

Sweetening agents can also be added to the pharmaceutical compositionand/or tablet and/or wet granulation formulation and/or rollercompaction formulation and/or direct compression formulation or to theouter core of the tablet to create or add to the sweetness. Saccharidefillers and binders, e.g. mannitol, lactose, and the like, can add tothis effect. For example, cyclamates, saccharin, aspartame, acesulfame K(Mukherjee (1997) Food Chem. Toxicol. 35:1177-1179), or the like (Rolls(1991) Am. J. Clin. Nutr. 53:872-878), can be used. Sweeteners otherthan sugars have the advantage of reducing the bulk volume of thepharmaceutical composition and/or tablet (core tablet and/or coat)and/or wet granulation formulation and/or roller compaction formulationand/or direct compression formulation and not affecting the physicalproperties of the tablet.

It will be understood by the skilled person that the incorporation ofone or more effervescent agents into the pharmaceutical composition maynecessitate the use of appropriate packaging. In a further aspect of theinvention, there is provided packaging suitable for a pharmaceuticalcomposition wherein the pharmaceutical composition comprises one or moreeffervescent agents. Examples of such packaging include packagingproviding moisture protection. Examples of such packaging include forexample PVC packaging, PVC/PVDC packaging, PVC/CTFE packaging,OPA/aluminium/PVC packaging, aluminium packaging or aluminium blisterpackaging. Further examples of such packaging include bottles with orwithout desiccants.

Compounds of the invention can be used to treat or prevent autoimmunediseases and/or symptoms of such diseases and are expected to be usefulas a therapeutic and prophylactic agent for diseases associated with anabnormal immune response (e.g. autoimmune diseases and allergicdiseases) and various infections and cancers which are required foractivation of an immune response. For example, compounds of theinvention may be administered to a mammal, including man, for thetreatment of the following non-limiting examples of autoimmuneconditions or diseases: rheumatoid arthritis, irritable bowel syndrome,systemic lupus erythematosus, multiple sclerosis, Hashimoto'sthyroiditis, Graves' disease, Addison's disease, diabetes mellitus,idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgEsyndrome, antiphospholipid syndrome and Sazary syndrome. Compounds ofthe invention may be administered to a mammal, including man, for thetreatment of the following non-limiting examples of cancers: treatmentof common cancers including prostate, breast, lung, ovarian, pancreatic,bowel and colon, stomach, skin and brain tumours and malignanciesaffecting the bone marrow (including the leukaemias) andlymphoproliferative systems, such as Hodgkin's and non-Hodgkin'slymphoma; including the prevention and treatment of metastatic diseaseand tumour recurrences, and paraneoplastic syndromes.

According to a further feature of the present invention there isprovided a method for treating an autoimmune disease state in a mammal,such as man, suffering from, or at risk of, said disease state, whichcomprises administering to a mammal in need of such treatment atherapeutically effective amount of a compound of Formula (I) and/or ahydrate thereof.

The invention also provides a compound of Formula (I) and/or a hydratethereof, for use in therapy.

In another aspect the invention provides the use of a compound ofFormula (I) and/or a hydrate thereof in the manufacture of a medicamentfor use in therapy.

In a further aspect, there is provided a method for treating rheumatoidarthritis in a mammal, such as man, suffering from, or at risk of, saiddisease state, which comprises administering to a mammal in need of suchtreatment a therapeutically effective amount of a compound of Formula(I) and/or a hydrate thereof.

The invention also provides a compound of Formula (I) and/or a hydratethereof, for use in the treatment of rheumatoid arthritis.

In another aspect the invention provides the use of a compound ofFormula (I) and/or a hydrate thereof in the manufacture of a medicamentfor use in the treatment of rheumatoid arthritis.

In a further aspect, there is provided a method for treating systemiclupus erythematosus in a mammal, such as man, suffering from, or at riskof, said disease state, which comprises administering to a mammal inneed of such treatment a therapeutically effective amount of a compoundof Formula (I) and/or a hydrate thereof.

The invention also provides a compound of Formula (I) and/or a hydratethereof, for use in the treatment of systemic lupus erythematosus.

In another aspect the invention provides the use of a compound ofFormula (I) and/or a hydrate thereof in the manufacture of a medicamentfor use in the treatment of systemic lupus erythematosus.

In a further aspect, there is provided a method for treating cancer in amammal, such as man, suffering from, or at risk of, said disease state,which comprises administering to a mammal in need of such treatment atherapeutically effective amount of a compound of Formula (I) and/or ahydrate thereof.

The invention also provides a compound of Formula (I) and/or a hydratethereof, for use in the treatment of cancer.

In another aspect the invention provides the use of a compound ofFormula (I) and/or a hydrate thereof in the manufacture of a medicamentfor use in the treatment of cancer.

Definitions

As used herein, the term “effervescent agent” refers to anypharmaceutically acceptable material which evolves a gas when placed inan aqueous environment, for example the evolution of carbon dioxide onacidification. An example of an effervescent agent is a carbonate, forexample a metal carbonate (such as sodium carbonate, potassiumcarbonate, magnesium carbonate, calcium carbonate or aluminiumcarbonate) or an organic carbonate (such as disodium glycine carbonate,dimethyl carbonate or ethylene carbonate). A further example of aneffervescent agent is a bicarbonate, for example a metal bicarbonate(such as sodium hydrogen carbonate or potassium hydrogen carbonate). Forthe avoidance of doubt, each of the effervescent agents referred toabove represents a separate and independent aspect of the invention.

In one particular aspect of the invention, the effervescent agent isselected from a carbonate or bicarbonate. In another particular aspectof the invention, the effervescent agent is selected from a metalcarbonate or a metal bicarbonate. In another particular aspect of theinvention, the effervescent agent is selected from sodium hydrogencarbonate, potassium hydrogen carbonate, magnesium carbonate or sodiumcarbonate. In a further particular aspect of the invention, theeffervescent agent is sodium hydrogen carbonate.

For the avoidance of doubt, reference to either a % w/w or to a weight(in mgs) of “one or more effervescent agents” in any aspect of theinvention refers to the combined total % w/w or the combined totalweight (in mgs) of all effervescent agents. By way of example, apharmaceutical composition comprising 10% w/w of sodium hydrogencarbonate and 10% w/w magnesium carbonate would comprise 20% w/w of “oneor more effervescent agents”.

As used herein, the term “binding agent” refers to a pharmaceuticallyacceptable compound or composition added to a formulation to hold theactive pharmaceutical ingredient and inactive ingredients together in acohesive mix. Dry binders used for direct compaction must exhibitcohesive and adhesive forces so that when compacted the particlesagglomerate. Binders used for wet granulation are hydrophilic andsoluble in water and are usually dissolved in water to form a wet massthat is then granulated. Examples of suitable binding agents includes,but are not limited to, Povidone, Plasdone K29/32, Plasdone S-630,hydropropyl cellulose, methylcellulose, polyvinylpyrrolidone, aluminiumstearate, hydroxypropylmethylcellulose and the like. It is possible forsuch binding agents to additionally act as water sequestering agents(e.g. Povidone).

As used herein, the term “filler” refers to any pharmaceuticallyacceptable material or composition added to a formulation to add bulk.Suitable fillers include, but are not limited to, mannitol, lactose,microcrystalline cellulose, silified microcrystalline cellulose anddicalcium phosphate.

As used herein, the term “lubricant” refers to any pharmaceuticallyacceptable agent which reduces surface friction, lubricates the surfaceof the granule, decreases tendency to build-up of static electricity,and/or reduces friability of the granules. Thus, lubricants can serve asanti-agglomeration agents. Examples of suitable lubricants are magnesiumstearate, stearic acid, sodium stearyl fumarate, colloidal silica, talc,other hydrogenated vegetable oil or triglycerides.

As used herein, the term “disintegrant” refers to materials added to thecomposition to help it break apart (disintegrate) and release themedicaments. Examples of disintegrants include, but are not limited to,non-saccharide water soluble polymers, such as cross-linked povidine.Other disintegrants that can also be used include, e.g. croscarmellosesodium, sodium starch glycolate, and the like, e.g. see Khattab (1992)J. Pharm. Pharmacol. 45:687-691.

The term “drying” and “dried” refer to a process which decreases thewater content of a composition to a desired level.

The terms “compressing”, “molding” and “pressing” refer to the processof applying compressive force to a formulation (powder or granules), aswithin a die, to form a tablet. The terms “compressed tablet” and“pressed tablet” mean any tablet formed by such a process.

The term “tablet” is used in its common context, and refers to a solidcomposition made by compressing and/or molding a mixture of compositionsin a form convenient for swallowing or application to any body cavity.

As used herein, “tablet strength” is the equivalent mass of the freeacid form of Compound I based on the amount of Formula (II) present inthe tablet. Thus by way of example, a tablet strength of 50 mg willcontain about 63 mg of Formula (II).

As used herein, “percent loading” is calculated by reference to theamount of Formula (II).

The term “low pH” refers to a measured pH of less than 5, such as lessthan 3, for example between 0 and 3.

The term “satisfactory in vitro dissolution” refers to a percentdissolution of greater than or equal to 70% within 30 minutes in 0.1Nhydrochloric acid solution at 37° C.+0.5° C. as measured using thegeneral procedure of the United States Pharmacopeia (Apparatus 2).

Dissolution Performance of the Existing Tablet

Reference Table 1 shows the composition of the tablet of Formula (II)with a tablet strength of 50 mg (the 50 mg tablet) as currentlyadministered in ongoing clinical trials together with an equivalenttablet of Formula (II) with a tablet strength of 100 mg (the 100 mgtablet). The tablets were prepared in accordance with WO2009/061909.

Tablet strength is the equivalent mass of the free acid form of CompoundI based on the amount of Formula (II) present in the tablet. Thus by wayof example, a tablet strength of 50 mg will contain about 63 mg ofFormula (II). The percent loading of Formula (II) in the 50 mg tablet is12.5% whereas the percent loading of Formula (II) in the 100 mg tabletis 25%.

REFERENCE TABLE 1 Material 50 mg tablet (% w/w) 100 mg tablet (% w/w)Formula (II) 12.5 25.0 Pregelatinised starch 37.02 30.77 Sodium starch5.77 5.77 glycolate Microcrystalline 37.02 30.77 cellulose Povidone 2.882.88 Magnesium stearate 0.96 0.96 Opadry II Blue 3.85 3.85 85F99003

Dissolution was determined according to the general procedure of theUnited States

Pharmacopeia using Apparatus 2 with 900 mL of 0.1N hydrochloric acidsolution at 37° C.±0.5° C. and stirrer speed of 75 rpm. At 5, 15, 30, 45and 60 minutes, 10 mL of dissolution solution was withdrawn and filteredthrough a 0.45 μM PTFE filter. The concentration of Formula (II) insolution was determined by uv spectroscopy (e.g. Agilent 8453) at awavelength of 324 nm and path length of 2 mm against an externalstandard solution.

Table 2 shows the resulting tablet percent dissolution in 0.1Nhydrochloric acid for the 50 mg reference tablet and for three separatebatches of the 100 mg tablet having the reference formulation set forthin Table 1 after 30 minutes. A plot showing the dissolution profile overtime is shown in FIG. 1.

TABLE 2 Mean % dissolution Formulation in 0.1N HCl at 30 Strength (mg)Formula (II) (% w/w) minutes 50  12.5 87 100 - A 25 65 100 - B 25 41100 - C 25 16

The 100 mg tablet exhibits unsatisfactory and/or variable dissolutionperformance (varying between 16% and 65%). This compares to the 50 mgtablet which exhibits satisfactory dissolution.

We have investigated a number of formulations where the percent loadingof Formula (II) is 25% or greater, in a desire to increase the meanpercent dissolution performance of a tablet which contains an increasedpercent loading of Formula (II). Mannitol, microcrystalline cellulose,silified microcrystalline cellulose, sodium chloride and di-sodiumhydrogen phosphate, and individual combinations thereof, all failed toprovide a percent dissolution in 0.1N hydrochloric acid after 30 minutesof greater than 50%. In addition, formulations which comprised citricacid, arginine, meglumine and Polyplasdone Crospovidine or combinationsthereof also failed to provide satisfactory dissolution.

It was therefore surprising to find that formulations which contained aneffervescent agent exhibited satisfactory dissolution, even where saidformulations contained an increased percent loading of Formula (II)(e.g. 25% and/or 37.5%, and up to 50%).

Table 3 shows the selection of components for sixteen separateexperiments to investigate dissolution in a tablet with an increasedpercent loading of Formula (II). The results are shown in FIG. 2. Table4 shows the selection of components for a further eight experiments andthe results for these are shown in FIG. 3. Tables 10 and 11 (in Example6) show the selection of components for a further twelve experiments andthe results for these are shown in FIG. 6. In each case, all experimentswhich did not use an effervescent agent failed to achieve a percentdissolution in 0.1N hydrochloric acid after 30 minutes of greater than50%. However, experiments which used an effervescent agent showedsatisfactory dissolution. For the avoidance of doubt, the reference towater in Tables 3 and 4 refers to the amount of water added during theprocessing of the formulation and prior to any subsequent drying step.The composition of any final tablet form will not include the level ofwater indicated.

TABLE 3 Formula Disintegrant SLS MgSt Water Run (II) (% w/w) Filler 1Filler 2 (5% w/w) (% w/w) (% w/w) (% w/w) 1 25.0 Mannitol Sodium SSG 0 115 Bicarbonate 2 25.0 Mannitol MCC CCS 0 1 35 3 37.5 SMCC Sodium SSG 0 125 Bicarbonate 4 37.5 Mannitol Sodium SSG 5 1 15 Bicarbonate 5 37.5 SMCCMCC CCS 0 1 55 6 37.5 SMCC MCC SSG 5 1 55 7 25.0 SMCC MCC CCS 5 1 55 825.0 Mannitol MCC SSG 5 1 35 9 25.0 SMCC Sodium CCS 0 1 40 Bicarbonate10 37.5 Mannitol Sodium CCS 0 1 25 Bicarbonate 11 25.0 SMCC MCC SSG 0 155 12 37.5 Mannitol MCC SSG 0 1 30 13 37.5 SMCC Sodium CCS 5 1 30Bicarbonate 14 25.0 SMCC Sodium SSG 5 1 30 Bicarbonate 15 37.5 MannitolMCC CCS 5 1 35 16 25.0 Mannitol Sodium CCS 5 1 15 Bicarbonate

TABLE 4 Cmpd I MCC Filler 1 PVP SSG MgSt Mannitol Water Run (% w/w) (%w/w) Filler 1 (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) 1 37.9 15disodium 30 3 5 1.5 7.1 22.5 hydrogen phosphate 2 37.9 0 disodium 10 3 51.5 42.1 20 hydrogen phosphate 3 37.9 0 sodium 30 3 5 1.5 22.1 15hydrogen carbonate 4 25.2 0 disodium 10 3 5 1.5 54.8 17.5 hydrogenphosphate 5 25.2 0 disodium 30 3 5 1.5 34.8 25 hydrogen phosphate 6 25.215 disodium 10 3 5 1.5 39.8 25 hydrogen phosphate 7 25.2 15 sodium 30 35 1.5 19.8 18.3 hydrogen carbonate 8 37.9 15 sodium 10 3 5 1.5 27.1 26.7hydrogen carbonate

Whilst we do not wish to be limited by theoretical considerations, theaddition of an effervescent agent (such as sodium hydrogen carbonate)appears to change the disintegration mechanism from a swellingdisintegration mechanism, wherein high drug loading prevents rapidhydration/swelling events and consequently leads to slowerdisintegrating tablets which only dissolves slowly, to an erosiondissolution mechanism. In particular, it is thought that incorporationof an effervescent agent (such as sodium hydrogen carbonate) allows thetablet to rapidly disintegrate (break) into small particles whichdissolve quickly.

Manufacturing Process

The particular manufacturing process of this invention for wetgranulation formulations comprises premixing all of the requiredformulation components except water and lubricant(s). In one preferredaspect, premixing is conducted in a mixer-granulator such as a PMA25,and premixing comprises mixing the components together at impellerspeeds ranging between about 50 to about 500 rpm for a period of betweenabout 2 to about 20 minutes. In another preferred aspect, batches weredry-blended for 4 minutes at 440 rpm with a chopper speed of 1500 rpmusing a Diosna granulator P1/6.

Water is then sprayed onto/into the dry composition to form a wetgranulation formulation described herein. The water is added at forexample a constant rate over a period of for example from about 0.05kg/min to about 1.0 kg/min with either constant mixing during additionor mixing after addition. In either event, mixing is continued until thewet granulation composition is homogenous. In an alternative aspect,water is added at a rate of 15 mL/min to a total volume of 8-12% (w/w).

The wet granulation formulation is then dried using conventionaltechniques to reduce water to a predetermined level. In one aspect, thewater content of the dried granulated formulation is less than about 10%(for example about 5%) by weight. Drying can be conducted at varioustemperatures and times. One skilled in the art could readily determinethe appropriate drying times based on the initial water content, thedesired final water content, and the drying temperature(s) employed.

The particular manufacturing process of this invention for rollercompaction formulations comprises preblending all of the requiredformulation components until homogenous. In one preferred aspect,preblending is conducted in a blender-granulator such as a Copley MobileBlender, and preblending comprises mixing the components together atspeeds ranging between about 50 to about 500 rpm for a period of betweenabout 2 to about 20 minutes.

The homogenous mix is then passed through a roller compactor, such as anAlexanderwerk WP120 to produce dry granules.

The dried granulated formulation produced via the wet granulation and/orroller compaction process is milled using conventional techniques andmachinery. In one aspect, the formulation is milled through anappropriate mesh screen using commercially available milling equipmentsuch as, e.g. Quadro Comil.

Following milling, the lubricant(s) (for example magnesium stearate) isadded to the granulated formulation which is then blended usingconventional techniques and machinery. Alternatively, the lubricant(s)(such as magnesium stearate) can be added to the dry granules prior tomilling.

The pressing or compressing of the dried, granulated, milled and blendedformulation can be accomplished using any tablet press. Many alternativemeans to effect this step are available, and the invention is notlimited by the use of any particular equipment. In one aspect, thecompression step is carried out using a Piccola Riva PV tablet press. Inanother aspect, the compression step is carried out by using an F3Manesty press.

The diameter and shape of the tablet depends upon the die and punchesselected for the compression of the milled and mixed formulation.Tablets can be discoid, oval, oblong, round, cylindrical, triangular,and the like. The tablets may be scored to facilitate breaking. The topor lower surface can be embossed or debossed with symbols or letters.

The compression force can be selected based on the type/model of press,a desired hardness of the resulting tabets, as well as other attributessuch as friability, disintegration or dissolution characteristics, etc.

The particular manufacturing process of this invention for directcompression formulations comprises preblending all of the requiredformulation components. In one preferred aspect, all of the requiredformulation components except lubricant(s) are mixed in amixer-granulator (such as a PMA25 at impeller speeds ranging betweenabout 50 to about 500 rpm for a period of between about 2 to about 20minutes), and thereafter lubricant(s) added and the resulting mixtureblended (using for example a WAB turbula at speeds ranging between about50 to about 500 rpm for a period of between about 2 to about 20minutes). The resulting mixture is then compressed into tablet coreusing conventional techniques.

DESCRIPTION OF FIGURES

FIG. 1 shows a plot of the percent dissolution in 0.1N hydrochloric acidof existing tablets of strength 50 mg and 100 mg versus time.

FIG. 2 shows a plot of the percent dissolution in 0.1N hydrochloric acidof sixteen alternative tablet forms versus time.

FIG. 3 shows a plot of the percent dissolution in 0.1N hydrochloric acidof a further eight alternative tablet forms versus time.

FIG. 4 shows a plot of the percent dissolution in 0.1N hydrochloric acidof eight tablet forms obtained via a roller compaction process versustime.

FIG. 5 shows a plot of the percent dissolution in 0.1N hydrochloric acidof a tablet form obtained via a direct compression process versus time.

FIG. 6 shows a plot of the percent dissolution in 0.1N hydrochloric acidof a further twelve alternative tablet forms versus time.

FIG. 7 shows a plot of weight loss versus time of five tablet formsafter placing the tablets in 0.1 N HCl (run 1).

FIG. 8 shows a plot of weight loss versus time of five tablet formsafter placing the tablets in 0.1 N HCl (run 2).

FIG. 9 shows a plot of weight loss versus time of five tablet formsafter placing the tablets in 0.1 N HCl (run 3).

EXAMPLES

The invention is further understood by reference to the followingexamples, which are intended to be purely exemplary of the invention.The present invention is not limited in scope by the exemplifiedaspects, which are intended as illustrations of single aspects of theinvention only. Various modifications of the invention in addition tothose described herein will become apparent to those skilled in the artfrom the foregoing description and accompanying figures. Suchmodifications fall within the scope of the appended claims.

In the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

-   -   GMP=good manufacturing practice    -   LOD=loss on drying    -   mg=milligram    -   MgSt=magnesium stearate    -   min=minute    -   mL=milliliter    -   nm=nanometer    -   JP=Japanese Pharmacopeia 15^(th) Edition, English Version        (Society of Japanese Pharmacopoeia) 2006    -   PhEur=European Pharmacopoeia 6^(th) Edition (Directorate for the        Quality of Medicines of the Council of Europe) 2009    -   PTFE=polytetrafluoroethylene    -   PVP=polyvinylpyrrolidone    -   rpm=revolutions per minute    -   SLS=sodium lauryl sulphate    -   SSG=sodium starch glycolate    -   USP—NF=United States Pharmacopeia 31/National Formulary 26 (The        United States Pharmacopeia Convention) 2008    -   uv=ultraviolet    -   w/w=weight for weight

Table 5 below shows materials used, pharmacopeial status, grade andsupplier.

TABLE 5 Material Pharmacopeia Grade Supplier Mannitol PhEur Pearlitol160c Roquette Freres USP-NF Pearlitol 120c S.A. (France) JP Parteck M200Cellulose, PhEur Avicel ® PH-101 FMC Biopolymer microcrystalline USP-NFAvicel ® PH-102 (Ireland) JP Sodium chloride Ph Eur Emprove MerckChemicals BP Ltd (UK) JP USP di-Sodium Ph Eur Emprove Merck Chemicalshydrogen BP Ltd (UK) phosphate USP Sodium Ph Eur Emprove Merck Chemicalshydrogen BP Ltd (UK) carbonate JP USP Sodium starch Ph Eur Glycolys LVRoquette Freres glycolate USP-NF S.A. (France) Croscarmellose Ph EurAc-di-Sol FMC Biopolymer sodium USP (Ireland) JP Magnesium Ph Eur NF NonBovine Mallinckrodt stearate USP-NF (USA) JP Povidone Ph Eur Kollidon 30BASF (Germany) USP K29/32 ISP (Germany) Sodium lauryl USP N/A SigmaAldrich sulphate NF (UK) (Sodium dodecyl sulfate) Silified Ph EurProsolv 50 JRS Pharma microcrystalline JP (Germany) cellulose NFPre-gelatinised Ph Eur Starch 1500 Colorcon (USA) starch 1500 NFColloidal silica USP-NF Aeorsil Evonik (Germany)

Table 6 below shows equipment used, model and supplier.

TABLE 6 Make Model Supplier Diosna P1/6 Dierks & Söhne Gmbh, Osnabrück,Germany Quadro Comil U3 & Quadro Engineering, Waterloo, Canada Comil 194WAB Turbula T2F Willy A. Bachofen AG, Muttenz, Switzerland Riva PiccolaNova RivaSA, Buenos Aires, Argentina Aeromatic Strea 1 CasburtPharmaceutical Equipment, Stoke-on-Trent, UK Alexanderwerk WP 120Alexanderwerk AG, Remscheid, Germany Copley Mobile Mobile CopleyScientific, Nottingham, UK Blender Blender Niro-Fielder PMA25 AeromaticFielder, Eastleigh, UK Fette 1200 Fette Compacting GmbH, Schwarzenbek,Germany Aeromatic- MP1 Aeromatic Fielder, Eastleigh, UK Fielder VectorMFL.01 Vector Corporation, Marion, IA, U.S.A F3 Manesty Manesty,Knowsley, UK

Example 1 Assessment of Dissolution Performance of Sixteen AlternativeTablet Forms

Sixteen different prototype tablets were prepared from a wet granulationformulation using methods well known to those skilled in the art. Thecomposition of each of these tablets is set out in Table 3 above (notincluding water).

Formula (II) and the excipients described in Table 3 (total batch sizeapproximately 250 g) are charged to a mixer-granulator (Diosna, 1 L) andmixed for 5 minutes at 300 rpm. Purified water (ranging from 15% w/w to55% w/was set out in Table 3) is added to the powders with furthermixing until a suitable wet mass is formed (ranging from 7 to 17 mins)at 300 rpm. The resultant granules are dried to appropriate moisturecontent (<6% LOD) using a fluid bed dryer (Vector) with an inlet airtemperature of 60° C. The dried granules are milled using anappropriately sized screen (1 mm, Quadro Comil U3). Magnesium stearateis then added to the granules, which are then blended (WAB turbula) for5 mins at 55 rpm before compressing into tablet cores using conventionaltabletting equipment (F3 tablet press).

Dissolution was determined in accordance with the procedure outlined inthe description above and the dissolution profiles are shown in FIG. 2.

Example 2 Assessment of Dissolution Performance of a Further EightAlternative Tablet Forms

A further eight different prototype tablets were prepared from a wetgranulation formulation using methods well known to those skilled in theart. The composition of each of these tablets is set out in Table 4above (not including water).

Formula (II) and the excipients described in Table 4 (total batch sizeapproximately 600 g) are charged to a mixer-granulator (Diosna, 4 L) andmixed. Purified water (ranging from 15% w/w to 26.7% w/was set out inTable 4) is added to the powders with further mixing until a suitablewet mass is formed (ranging from 10 to 24 mins) at 200 rpm. Theresultant granules are dried to appropriate moisture content (<5% LOD)using a fluid bed dryer (Aeromatic Strea) with an inlet air temperatureof 100° C. The dried granules are milled using an appropriately sizedscreen (1 mm, Quadro Comil U3). Magnesium stearate is then added to thegranules, which are then blended (WAB turbula) for 10 mins at 50 rpmbefore compressing into tablet cores using conventional tablettingequipment (Riva Piccola).

Dissolution was determined in accordance with the procedure outlined inthe description above and the dissolution profiles are shown in FIG. 3.

Example 3 Assessment of Dissolution Performance of Tablets of Formula(II) Prepared by Roller Compaction Process

Eight formulations selected from Examples 2 and 3 were assessed forfeasibility in a roller compaction process using methods well known tothose skilled in the art. The composition of each of these formulationsis set out in Table 7 below. Formula (II) and the excipients describedin Table 7 (total batch size approximately 1.5 kg) are charged to amixer to produce a homogenous mix (Copley Mobile Blender) for 5 minutesat 30 rpm. The homogeneous mix is then passed through a roller compactor(Alexanderwerk, 40 mm roller size, 25 bar roller pressure, 2.5 rpmroller speed, 2.0 mm roller-gap size) to produce dry granules. The drygranules are then blended with magnesium stearate (Copley MobileBlender). The resultant granules are compressed into tablet cores usingconventional tabletting equipment (Riva Piccola).

TABLE 7 Formulation (% w/w) Component 1 2 3 4 5 6 7 8 Formula (II) 37.925.2 37.9 37.9 37.9 37.9 37.9 37.9 Mannitol 22.1 54.8 27.1 27.1 45.145.1 42.1 45.1 (Silicified) 0 0 15 15 10 10 10 10 Micro- crystallinecellulose Sodium 30 10 10 10 0 0 0 0 hydrogen carbonate Povidone 3 3 3 30 0 3 0 Sodium Starch 5 5 5 5 5 5 5 5 glycolate Colloidal silica 0.5 0.50.5 0.5 0.5 0.5 0.5 0.5 Intragranular 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5Magnesuim Stearate Extragranular 1 1 1 1 1 1 1 1 Magnesuim Stearate

Formulations 1, 2, 3 and 8 were manufactured using Pearlitol 160 C. Theremaining formulations used Parteck M200 mannitol. Formulations 3, 4, 6and 7 used microcrystalline cellulose (Avicel PH101). Formulations 5 and8 used silicified microcrystalline cellulose (Prosolv 50).

Dissolution was determined in accordance with the procedure outlined inthe description above and the dissolution profiles are shown in FIG. 4.

Example 4 Assessment of Dissolution Performance of Tablets of Formula(II) Prepared by Direct Compression

Tablets were prepared using direct compression formulation using methodswell known to those skilled in the art. The composition of the tabletsis as per Table 3, Run 9 above (without the addition of water).

Formula (II) and the excipients described in Table 3, Run 9 (total batchsize approximately 250 g) are charged to a mixer-granulator (Diosna, 1L) and mixed for 5 minutes at 300 rpm. Magnesium stearate is then addedto the blend, which is then blended (WAB Turbula) for 5 minutes at 55rpm before compressing into tablet cores using conventional tablettingequipment (F3 tablet press).

Dissolution was determined in accordance with the procedure outlined inthe description above and the dissolution profiles are shown in FIG. 5.

Example 5 Preparation of Tablets of Formula (II)

Tablets containing the components set out in Table 8 below were preparedusing methods well known to those skilled in the art, in particularusing conventional mixing, wet granulation, compression and film coatingprocesses, according to GMP.

Formula (II), mannitol, sodium hydrogen carbonate, sodium starchglycolate and povidone are charged to a mixer-granulator (PMA25) andmixed. Purified water is added to the powders with further mixing untila suitable wet mass is formed. The wet mass may be passed through ascreen to break up any large agglomerates. The resultant granules aredried to appropriate moisture content (<5% LOD) using a fluid bed dryer(MP1). The dried granules are milled using an appropriately sized screen(for example 1.1 mm, Comil 194). Magnesium stearate is then added to thegranules, which are then blended (Copley) before compressing into tabletcores using conventional tabletting equipment (Fette 1200).

TABLE 8 Tablet strength 50 mg 100 mg 150 mg Components mg/tabletmg/tablet mg/tablet Standard Formula (II) 63.1 126.2 189.3 AstraZenecaMannitol 61.8 248.6 185.3 Ph Eur, NF, JP Sodium hydrogen 25.0 75.0 74.9Ph Eur, USP, JP carbonate Sodium starch 8.3 25.0 25.0 Ph Eur, NFglycolate Povidone 5.0 15.0 15.0 Ph Eur, USP, JP, NF Magnesium 3.3 10.010.0 Ph Eur, NF stearate

Example 6 Assessment of Dissolution Performance of Additional TabletForms

Potassium hydrogen carbonate (KHCO₃), magnesium carbonate (MgCO₃) andsodium carbonate (Na₂CO₃) were incorporated into the tablet formulationin place of sodium hydrogen carbonate. The level of each was correctedto evolve the same quantity of carbon dioxide.

Sodium carbonate (Na₂CO₃) was incorporated at two concentrations toprovide better understanding of the mechanism of action of theseeffervescent agents in the formulation. This took advantage of the factthat the reaction of sodium carbonate with hydrochloric acid takes placein two stages:

Stage I: sodium carbonate is converted to sodium hydrogen carbonate(NaHCO₃) as shown in the reaction:Na₂CO₃+HCl→NaHCO₃+NaCl

Stage 11: the gas, carbon dioxide is releasedNaHCO₃+HCl→NaCl+H₂O+CO₂

Accordingly, sodium carbonate has stronger alkalizing activity comparedto sodium hydrogen carbonate due to its capability to accept twohydrogen ions but has slower effervescent activity as evolution of thegas (CO₂) requires two steps reaction to take place.

Therefore, two levels of sodium carbonate were investigated. The lowerlevel (9.5%) gave similar alkalisation capacity to 15% sodium hydrogencarbonate but with a lower amount of CO₂ to evolve in acidicenvironment. The higher level (15%) evolved the same total amount of CO₂as 15% sodium hydrogen carbonate but at slower rate and with higheralkalisation capacity.

In addition, arginine and meglumine were investigated as alternatives tosodium hydrogen carbonate. Arginine and meglumine provide alkalisingactivity without any effervescent activity.

Moreover, citric acid was incorporated in one formulation to provideacidity to the microenvironment of the tablets and counteract thealkalising effect of sodium hydrogen carbonate. The level of citric acidwas adjusted to neutralise the alkalinity of sodium hydrogen carbonate.

Furthermore, incorporation of higher levels of Formula (II) in theformulation was included at two levels of sodium hydrogen carbonate, 15%and 25%, to address possible correlation between the quantities ofFormula (II) and the quantity of sodium hydrogen carbonate required toallow satisfactory dissolution.

Additionally, Polyplasdone® Crospovidone superdisintegrant wasinvestigated in the formulation to replace sodium hydrogen carbonate andsodium starch glycolate in order to provide the possibility for rapiddisintegration through a combination of swelling and wicking mechanismof disintegrations. Polyplasdone disintegrants are highly compressiblematerials and therefore higher level could be used to provide quickerdisintegration. Polyplasdone® Crospovidone was investigated at twoconcentration 10% and 15%. Meglumine was included in these twoformulations to provide high local pH (to prevent active pharmaceuticalingredient (API) gelling in acidic environment) and consequentlyoffering a better opportunity to achieve complete dissolution in acid.

The formulation components and composition for each of the alternativetablet forms in Example 6 are presented in Tables 9, 10 and 11.

TABLE 9 Component Supplier/Trade name Function Formula (II)AstraZeneca/DSM Linz Active Pharmaceutical Ingredient Mannitol RoquettePearlitol 50C Filler sodium hydrogen Merck Emprove effervescent/carbonate (NaHCO3) alkalizing agent Potassium hydrogen Merck EMPROVE ®exp effervescent/ carbonate (KHCO3) Ph Eur, BP, USP, FCC, E501alkalizing agent magnesium carbonate Merck Emprove, Heavy effervescent/(MgCO3) alkalizing agent sodium carbonate Merck EMPROVE ® expeffervescent/ (Na2CO3) Ph Eur, BP, NF, anhydrous alkalizing agent CitricAcid Merck EMPROVE ® exp Acidifying agent Ph Eur, BP, JP, USP, E 330,FCC, anhydrous L-arginine (Arg) Merck EMPROVE ® exp alkalizing agent PhEur, USP Meglumine (Megl) Merck EMPROVE ® api alkalizing agent Ph Eur,JP, USP Crospovidone Polyplasdone ® Disintegrant (CrosPosv) CrospovidoneSodium Starch Expltab Disintegrant Glycolate (SSG) PolyvinylpyrrolidoneBASF Kollidon K30 Binder (PVP) Magnesium Stearate Mallinkrodt non-bovineLubricant (MgSt)

TABLE 10 Run 1 2 3 4 5 6 7 8 9 10 11a 11b Formula (II) (%) 37.9 37.937.9 37.9 37.9 37.9 37.9 37.9 37.9 37.9 50 50 NaHCO3 (%) 15 0 0 15 0 0 00 0 0 15 25 Na2CO3 (%) 0 15 9.465 0 0 0 0 0 0 0 0 0 Citric acid (%) 0 00 34.305 0 0 0 0 0 0 0 0 KHCO3 (%) 0 0 0 0 17.88 0 0 0 0 0 0 0 MgCO3 (%)0 0 0 0 0 15.06 0 0 0 0 0 0 Arg (%) 0 0 0 0 0 0 31.1 0 0 0 0 0 Megl (%)0 0 0 0 0 0 0 34.86 34.86 34.86 0 0 CrosPove (%) 0 0 0 0 0 0 0 0 10 15 00 SSG (%) 5 5 5 5 5 5 5 5 0 0 5 5 PVP (%) 3 3 3 3 3 3 3 3 3 3 3 3 MgSt(%) 2 2 2 2 2 2 2 2 2 2 2 2 Mannitol (%) 37.1 37.1 42.64 2.795 34.2237.04 20.99 17.24 12.24 7.24 25 15

Batches of drug substance and excipients were dispensed to form a totalnominal batch size of 600 g (Table 11). Magnesium stearate was includedin the nominal total but was not included during granulation. Followingdrying, magnesium stearate was added to make up 2% of the total drygranules.

A wet granulation process was used to prepare the granules fortabletting using the method below.

-   -   Batches were dry blended for 4 min at 440 rpm with chopper speed        of 1500 rpm using Diosna granulator P1/6 (Dierks & Söhne Gmbh,        Osnabruck, Germany) in the 4 L bowl.    -   Water was added drop wise at a rate of 15 mL.min-1 to a total        volume of 8-12% (w/w). The endpoint was checked by passing a        sample of powder through a 1 mm sieve and judging whether there        were fines and whether most of the materials were granular.    -   The wet mass was dried using Niro-Aeromatic Strea fluid bed        dryer (Casburt Pharmaceutical Equipment, Stoke-on-Trent, UK)        with a maximum inlet temperature of 90° C. and an appropriate        fluidizing airflow. Extent of drying was determined using a        moisture analyser (Mettler Toledo HB43) to <2%.    -   The dried granular mass was milled at 3000 rpm through a 1.0 mm        screen using a U3 bench top Quadro Comil mill (Quadro        Engineering, Waterloo, Canada).    -   The lubricant was then added at level of 2% by weight of the        dried mass of granules and was blended using a Turbula blender        (Willy A. Bachofen A G, Muttenz, Switzerland) at 50 rpm for 15        min.    -   The resultant mixtures were compressed using an F3 Manesty press        (Casburt Pharmaceutical Equipment, Stoke-on-Trent, UK). The        target compression force was 14 kN as used during A23        [RITA.000-376-136]. The compression force was assessed using        DAAS instrumentation (Waltti Electronics Ltd., Kuopio, Finland).    -   Batches were compressed using 11 mm round concave tooling.        Tablets were compressed to a target weight of 500 mg. Some        tablets were collected from the line to allow weight and        hardness to be correlated with compression force.    -   The resultant tablets were de-dusted and kept in air tight        plastic bottles for analysis.

TABLE 11 1 2 3 4 5 6 7 8 9 10 11a 11b Formula (II) (g) 227.4 227.4 227.4227.4 227.4 227.4 227.4 227.4 227.4 227.4 300 300 NaHCO3 (g) 90 0 0 90 00 0 0 0 0 90 150 Na2CO3 (g) 0 90 56.79 0 0 0 0 0 0 0 0 0 Citric acid (g)0 0 0 205.83 0 0 0 0 0 0 0 0 KHCO3 (g) 0 0 0 0 107.28 0 0 0 0 0 0 0MgCO3 (g) 0 0 0 0 0 90.36 0 0 0 0 0 0 Arg (g) 0 0 0 0 0 0 186.66 0 0 0 00 Megl (g) 0 0 0 0 0 0 0 209.16 209.16 209.16 0 0 CrosPove (g) 0 0 0 0 00 0 0 60 90 0 0 SSG (g) 30 30 30 30 30 30 30 30 0 0 30 30 PVP (g) 18 1818 18 18 18 18 18 18 18 18 18 MgSt (g) 12 12 12 12 12 12 12 12 12 12 1212 Mannitol (g) 222.6 222.6 255.8 16.77 205.3 222.2 125.9 103.4 73.4443.44 150 90

Disintegration time was measured using an Erweka Copley ZT74disintegration machine. The experiment was carried out at 36-38° C.using 0.7 L tap water and the disc method. Six tablets were tested foreach batch. Results are presented as mean±SD (n=6).

Sotax HT100 was used to determine the weight, hardness, thickness anddiameter of 15 tablets from each batch. The Sotax is an automated tablettester, which measures each parameter at a different station for aspecified number of tablets using a specific method (“11 mm 500 mg RoundUncoated n15”). First the weight is measured, then the tablet is passedto a thickness gauge before being passed to a jaw where the diameter andhardness are measured. A report is then generated with individual datafor each of the tablets tested, as well as the calculated mean and RSDfor each batch. Results are presented as mean±SD (n=15).

The true density of the tablets was obtained by helium pycnometry usingthe AccuPyc. Ten tablets were weighed accurately, placed in the samplecup previously used for calibration and analysed. True density wascalculated for each batch using the equation set out below and was foundto be between 1.55 and 1.56 g/cc for each of them.True density=(mass/volume of solids)

Tablet envelope density (apparent density) was then obtained by a volumedisplacement method using the GeoPyc. The same ten tablets were thenplaced in the 25.4 cm cylinder with DryFlo. The porosity was calculatedby the GeoPyc using the true density data from above and the followingequation:Apparent density=(mass of tablets/envelope volume of tablets)

The porosity of the tablets was then determined using the apparentdensity and true density calculated above in the following equation:Porosity=100×1−(apparent density/true density)

Dissolution was determined in accordance with the procedure outlined inthe description above.

The amount of gas evolved as a result of the tablets being placed in anacidic environment was assessed. A 250 ml beaker filled with 100 ml of0.1 N HCl (pH 1) was placed over a balance connected to a PC to transmitthe weight at regular time interval (every 15 seconds). The balance wasleft to settle until the balance reading was stable. One tablet wasdropped in the beaker and weight recording was started. The weightdifference was calculated and plotted as a function of time.

Weight, hardness, disintegration time and porosity data are summarisedin Table 12.

TABLE 12 Disintegration Weight (mg) Hardness (kp) time (s) Porosity (%)Average SD Average SD Average SD Average SD 1 500.3 5.00 9 0.9 327.525.03 13.10 0.39 2 501.6 10.43 9 2.4 475.5 43.72 15.43 0.37 3 476.315.86 7 2.7 426.16 39.42 13.90 0.23 5 505.4 3.08 9 0.7 454 23.41 12.660.33 6 487.2 13.03 10 2 134 9.01 15.99 0.06 7 493 19.53 8 2.7 338 10.1214.62 0.29 8 491.1 26.68 11 3.1 360.0 26.50 10.33 0.10 9 509.2 6.17 151.7 367.0 97.6 9.18 0.14 10  499.1 7.72 9 1.1 516.7 15.2 14.66 0.14 11a504.4 12.29 9 2.2 461.3 19.2 14.19 0.05 11b 499.4 16.9 9 2 487.2 56.412.66 0.17

The dissolution profiles of the tablets in 0.1 M HCl are presented inFIG. 6. No result is given for Run 4 as no satisfactory formulationcould be achieved and therefore no dissolution measurement was taken.

Results from gas evolution quantification are presented in FIGS. 7, 8and 9.

The results showed that alkalising agents which did not additionallyprovide effervescent activity failed to provide tablets of Formula (II)which gave satisfactory dissolution. The results suggest thateffervescent agents such as sodium hydrogen carbonate, potassiumhydrogen carbonate and magnesium carbonate enhance the dissolution ofthe tablet.

The tablet with a lower level of sodium carbonate provided a lower levelof dissolution compared to the tablet with a higher level of sodiumcarbonate. Furthermore, the tablet with the higher level of sodiumcarbonate provided dissolution at a lower rate and extent compared totablets with sodium hydrogen carbonate. This could be explained as aresult of slower carbon dioxide evolution.

Accordingly, the rate and extent of carbon dioxide evolution appear toeffect the dissolution profile of the tablet.

The results further show that increased drug loading (for examplegreater than or equal to 50% w/w of Formula (II)) exhibiting asatisfactory dissolution profile can be achieved using sodium hydrogencarbonate. Furthermore, the results show that higher levels of sodiumhydrogen carbonate (greater than or equal to 25%) were not necessary toachieve a satisfactory dissolution profile.

The invention claimed is:
 1. A solid pharmaceutical compositioncomprising greater than 15% w/w of the compound of Formula (I):

wherein each X⁺ represents a monovalent cation; and/or a hydratethereof; and an amount of one or more effervescent agents that issufficient to provide satisfactory in vitro dissolution at low pH; andfurther comprising one or more pharmaceutically acceptable ingredients.2. The solid pharmaceutical composition according to claim 1 comprisinggreater than or equal to 25% w/w of the compound of Formula (I) and/orhydrate thereof.
 3. The solid pharmaceutical composition according toclaim 1 comprising less than or equal to 20% w/w of the effervescentagent.
 4. The solid pharmaceutical composition according to claim 1wherein the effervescent agent is sodium hydrogen carbonate.
 5. Thesolid pharmaceutical composition according to claim 1 wherein each X⁺ inthe compound of Formula (I) represents a sodium cation (Na⁺).
 6. Thesolid pharmaceutical composition according to claim 1 wherein thecompound of Formula (I) is in the form of an hexahydrate.
 7. The solidpharmaceutical composition according to claim 1 wherein the compound ofFormula (I) is in the form of Formula (II):


8. A unit dosage form comprising greater than or equal to 60 mg of thecompound of Formula (I):

wherein each X⁺ represents a monovalent cation; and/or a hydratethereof; and less than or equal to 110 mg of one or more effervescentagents that is sufficient to provide satisfactory in vitro dissolutionat low pH; and further comprising one or more pharmaceuticallyacceptable ingredients.